Duff was taught playing the bass by his older brother Bruce and during his teenager years, he was in several bands on various intstruments. In 1979, Duff McKagan formed the Punk group The Vains and one year later, the single „School Jerks“ was released. In 1980 he joined the Fastbacks as their drummer, and two years later he became the guitarist of the Hardcore band The Fartz, which evolved into 10 Minute Warning.

In 1983, McKagan moved to Los Angeles, where he met guitarist Slash and drummer Steven Adler. This trio founded the group Road Crew, but it was very difficult to find a good singer so the band called it a day very soon. In June 1985, Duff became the new bass player in Guns N‘ Roses – a Hardrock group, which was founded by singer Axl Rose and guitarist Izzy Stradlin. Shortly after that, also Slash and Steven Adler joined, and on the 21st July 1987 the legendary debut album „Appetite for Destruction“ was released. This LP became the best-selling debut album of all time in the USA, by selling 18 million units.

Until the big line up change (Axl Rose is the only founding member – Slash left in October 1996) in 1997, Duff McKagan was the bass player for Guns N‘ Roses.

Duff already founded the band Neurotic Outsiders with Steve Jones (Sex Pistols), John Taylor (Duran Duran) and Matt Sorum, before he officially quit the Gunners. The quartet released the self-titled album in 1996. One year later, this supergroup was history and McKagan moved back to Seattle, where he reunited 10 Minute Warning again. In 1998, this band broke-up and Duff concentrated more on his solo career. Beside several projects, McKagan founded with his mates Slash and Matt Sorum the group Velvet Revolver. Guitarist Dave Kushner and singer Scott Weiland completed the line-up and the albums „Contraband“ and „Libertad “ were released. In 2008, Weiland left to reunite his old band Stone Temple Pilots. Until today, Duff is playing in several bands and he also reunited with Guns N‘ Roses for some shows.